Consanguinity-linked genetic variants in Algerian patients with steroid-resistant nephrotic syndrome: a familial...

Steroid-resistant nephrotic syndrome (SRNS) is a severe glomerular disorder frequently progressing to kidney failure, particularly in children. Data on the genetic landscape of SRNS in North African populations, particularly in Algeria, where consanguinity rates are high, remain scarce. This study aimed to investigate the genetic etiology of familial SRNS in a large cohort of Algerian patients using targeted next-generation sequencing (NGS), to bridge the current diagnostic gap and better understand the molecular basis of SRNS in consanguineous populations.

We conducted a comprehensive genetic analysis of 102 Algerian patients (85 children and 17 adults) from 42 consanguineous families diagnosed with familial SRNS. All participants underwent NGS using a panel of 58 known SRNS-associated genes, followed by Sanger confirmation of selected variants.

Pathogenic or likely pathogenic variants were identified in 5 children carrying heterozygous TRPC6 variants, 35 children carrying homozygous variants in PLCE1, COQ6, NPHS1, CD2AP, NPHS2, or WDR73, 1 adult carrying a heterozygous TRPC6 variant, and 5 adults carrying homozygous variants in LAMB2, PLCE1, or NPHS2. No compound heterozygous variants were detected. In total, pathogenic or likely pathogenic variants were identified in 40 of 85 pediatric patients (47.1%) and in 6 of 17 adult patients (35.3%). In children, non-syndromic SRNS was the predominant phenotype, while syndromic forms accounted for a substantial proportion of cases. The most frequently mutated genes in the pediatric cohort were NPHS2 (16.5%, 14/85), followed by NPHS1 (10.6%, 9/85), PLCE1 (8.2%, 7/85), TRPC6 (5.9%, 5/85), COQ6 (3.5%, 3/85), CD2AP (1.2%, 1/85), and WDR73 (1.2%, 1/85). In the adult cohort, the most frequently affected gene was NPHS2 (17.6%, 3/17), followed by PLCE1, LAMB2 and TRPC6 (each 5.9%, 1/17).

The results reveal a high burden of consanguinity-linked monogenic variants in Algerian patients with SRNS, especially in children, highlighting the predominance of recessive inheritance and the contribution of TRPC6. These findings underscore the importance of early genetic screening in guiding clinical management, particularly in consanguineous populations.